DESCRIPTION: It is generally believed that the cochlea is able to encode sound stimuli by using an active negative damping mechanism to overcome problems inherent in the physical constraints of the system. This active process is responsible for the sharp tuning and low thresholds observed in the response to auditory stimuli. Outer hair cells (OHCs) are the cellular elements responsible for generating the active process and are under the influence of descending efferent fibers originating in the brainstem. Numerous studies have shown that the major neurotransmitter at the OHC/efferent terminal synapse is ACh. We have cloned a novel ACh receptor, designated [alpha]9, which has the same pharmacological profile as that reported earlier for the OHC cholinergic receptor. In order to better understand how cochlear functions are accomplished, a study of the [alpha]9 nAChR subunit is necessary. Efferent effects on the cochlea have usually been studied through electrical stimulation of the olivocochlear bundle (OCB). However, in order to elicit a response, high stimulus rates must be used which are higher than the natural OCB activity. Another way to study the effects of efferent activation on the cochlea (and thus the study of the OHC-efferent fiber synapse) has been to pharmacologically manipulate the system, but the selectivity and specificity of drugs is always a concern in vivo. Therefore, in order to directly examine the role [alpha]9 has in the cochlea, we have designed a series of experiments which make use of animals carrying null allele mutations for the [alpha]9 gene. Our long-term goal is to understand the cochlear efferent system and how it contributes to normal hearing processes. Thus, we will begin a series of investigations into the anatomical and physiological consequences of [alpha]9 ablation.